REVIEW ARTICLE

Molecular mechanism of obesity-induced

‘metabolic’ tissue remodeling
Miyako Tanaka1, Michiko Itoh2, Yoshihiro Ogawa1,3,4,5,6, Takayoshi Suganami1*
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Departments of 2 Organ Network and Metabolism,
3
Molecular Endocrinology and Metabolism, 4Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo,
5
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, and 6Japan Agency for Medical Research and Development,
CREST, Tokyo, Japan

Keywords ABSTRACT
Chronic inflammation, Obesity, Chronic inflammation is a common molecular basis underlying a variety of chronic
Macrophages diseases. Accumulating evidence has also suggested that chronic inflammation contributes
to the pathogenesis of obesity and diabetes, which have been considered as metabolic
*Correspondence diseases. For the past several decades, there has been dramatic progress in understanding
Takayoshi Suganami the underlying mechanism of adipose tissue dysfunction induced by obesity. Tissue
Tel.: +81-52-789-3881 remodeling is one of the histological features of chronic inflammation, in which stromal
Fax: +81-52-789-5047
cells dramatically change in number and cell type. Indeed, adipose tissue remodeling is
E-mail address:
induced by various stromal cells, and results in the impairment of adipose tissue function,
suganami@riem.nagoya-u.ac.jp
such as adipocytokine production and lipid storage, which leads to systemic metabolic
J Diabetes Investig 2018; 9: 256–261 disorder. In addition to adipose tissue, the liver is another example of obesity-induced tis-
sue remodeling. In the present review, we discuss how obesity induces interstitial fibrosis
doi: 10.1111/jdi.12769 in adipose tissue and the liver, particularly focusing on the role of macrophages.

INTRODUCTION acute and chronic inflammation. In this regard, tissue remodel-

Chronic inflammation is a common molecular basis underlying
a variety of chronic diseases, such as atherosclerotic disease,
autoimmune disease, neurodegenerative disease and cancer.
Accumulating evidence has also suggested that chronic inflam-
mation plays a crucial role in obesity and diabetes pathogenesis,
which have been considered as metabolic diseases. There are a
large number of studies on the effect of excessive energy intake
and nutritional imbalance on chronic inflammation and
impairment of metabolic homeostasis. In this regard, one of the
most important organs is adipose tissue, which senses nutri-
tional conditions in our body and stores the excessive energy as
triglyceride. Adipose tissue also regulates inflammatory
responses and secretes various bioactive molecules, which are
termed ‘adipocytokines’ or ‘adipokines,’ in response to the sys-
temic nutritional status, resulting in a feedback mechanism of
metabolic homeostasis1–6. In obesity, these adipose tissue func-
tions become impaired, which gives rise to systemic metabolic
derangements (metabolic syndrome).
In contrast to acute inflammation, typical signs of ‘inflamma-
tion,’ such as pain, heat, redness and swelling, are rarely
observed in chronic inflammation. In contrast, pro-inflamma-
tory cytokines and immune cells are a common mechanism of
Received 16 October 2017; accepted 25 October 2017
ing is one of the histological features of chronic inflammation,
in which stromal cells dramatically change in number and cell
type7. In most cases, chronic inflammation finally results in
tissue fibrosis and organ dysfunction. In addition to adipose tis-
sue, the liver is another example of obesity-induced tissue
remodeling. Lipid accumulation in the liver or non-alcoholic
fatty liver disease (NAFLD) is a hepatic feature of the metabolic
syndrome. In particular, non-alcoholic steatohepatitis (NASH),
characterized by chronic inflammation and pericellular fibrosis,
increases the risk of cirrhosis and hepatocellular carcinoma8,9.
In the present review article, we discuss the recent progress in
the understanding of the molecular mechanism of obesity-
induced tissue remodeling, especially focusing on adipose tissue
and liver.
OBESITY-INDUCED ADIPOSE TISSUE INFLAMMATION
The adipose tissue includes not only lipid-laden mature adipo-
cytes, but also numerous stromal cells, such as preadipocytes,
fibroblasts, endothelial cells and immune cells. During the
development of obesity, adipose tissue shows dynamic histologi-
cal changes characterized by adipocyte hypertrophy, increased
angiogenesis, immune cell infiltration and extracellular matrix
overproduction2,6,10,11. These changes are reminiscent of ‘vascu-
lar remodeling,’ which is the chronic inflammatory responses

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in atherosclerotic vascular walls. It is well understood that ‘vas-
cular remodeling’ is caused by the complex interactions among
various cells, such as vascular endothelial cells, vascular smooth
muscle cells, lymphocytes and monocyte-derived macrophages5,
so the dynamic change observed in obese adipose tissue can be
referred to as ‘adipose tissue remodeling,’ which should be
involved in the pathogenesis of obesity-induced adipose tissue
dysfunction. Furthermore, there is considerable evidence sug-
gesting that adipocytokine production and lipid storage are reg-
ulated by the interaction of mature adipocytes and stromal cells
in adipose tissue12,13.
Since ground-breaking reports published in 2003–2004
showed that macrophages infiltrate into obese adipose tissue in
mice and humans14–16, the role of macrophages among the var-
ious types of stromal cells in obese adipose tissue has been
most intensively studied. The macrophages form a unique his-
tological structure termed crown-like structure (CLS), where
CD11c-positive macrophages surround dead or dying adipo-
cytes to engulf the dead adipocytes and the residual lipid17. In
addition, the heterogeneity of macrophages in obese adipose tis-
sue has also been pointed out: pro-inflammatory M1 or ‘classi-
cally activated’ macrophages, and anti-inflammatory M2 or
‘alternatively activated’ macrophages18,19. We and others have
shown that chemokines, such as monocyte chemoattractant
protein-1, recruit M1 macrophages from the bone marrow to
form CLS20–22. As pro-inflammatory cytokines, such as tumor
necrosis factor-a, are produced by M1 macrophages in obese
adipose tissue and their number is positively correlated with
adiposity and systemic insulin resistance23,24, CLS is a hallmark
of adipose tissue inflammation. Of note, we previously reported
that Toll-like receptor 4 deficiency inhibits the increase of the
M1-to-M2 ratio of macrophages in diet-induced obese mice,
without affecting the number of CLS25. It is also known that
Toll-like receptor 4-deficient mice are protected against obesity-
induced insulin resistance26,27. By contrast, M2 macrophages
are observed diffusely in interstitial spaces between
adipocytes18,19. Thus, the M1-to-M2 ratio of macrophages, in
addition to the number of macrophages, critically regulates
obesity-induced inflammatory changes in adipose tissue.
PARACRINE INTERACTION BETWEEN ADIPOCYTES AND
MACROPHAGES
As chronic inflammation is characterized by sustained interac-
tion of various cell types, it is important to understand how
adipocytes and macrophages cross-talk with each other. We
have provided evidence suggesting that a paracrine loop involv-
ing mature adipocytes-derived saturated fatty acids and macro-
phages-derived tumor necrosis factor-a establishes a vicious
cycle to exaggerate chronic inflammation28. Indeed, infiltrated
macrophages in obese adipose tissue produce tumor necrosis
factor-a, which can induce the production of pro-inflammatory
cytokine and lipolysis of adipocytes. The released high concen-
trations of free fatty acids, particularly saturated fatty acids,
such as palmitate, might induce inflammatory responses in
ª 2017 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
REVIEW ARTICLE
Obesity and metabolic tissue remodeling
macrophages29,30. As a molecular mechanism, saturated fatty
acids activate the Toll-like receptor 4 signaling and the inte-
grated stress response in macrophages to produce pro-inflam-
matory cytokines31. In contrast, x-3 or n-3 polyunsaturated
fatty acids, such as eicosapentaenoic acid (EPA), strongly antag-
onize the inflammatory effects of saturated fatty acids on
macrophages. Consistently, dietary supplementation of EPA
effectively reverses the macrophage polarity from M2 to M1 in
obese adipose tissue, without affecting the macrophage popula-
tion32. Thus, the cross-talk between adipocytes and macro-
phages maintains chronic inflammatory changes of obese
adipose tissue.
MOLECULAR MECHANISM OF ADIPOSE TISSUE
REMODELING
Similar to other chronic inflammatory diseases, obesity-induced
chronic inflammation in adipose tissue eventually leads to inter-
stitial fibrosis in rodent models and humans33–36. As it is
known that interstitial fibrosis is a common pathway to end-
stage organ failure, it might cause obesity-triggered adipose tis-
sue dysfunction. For instance, a recent report suggested that
there is a negative correlation between adipose tissue fibrosis
and adipocyte diameters in human adipose tissue37, suggesting
the role of interstitial fibrosis in adipose tissue expandability
during the development of obesity. Interestingly, Khan et al.33
reported that mice lacking collagen VI, which is expressed
abundantly in adipose tissue, show uninhibited adipose tissue
expansion and substantial improvement in insulin sensitivity
when consuming a high-fat diet. A fundamental function of
adipose tissue is to store excessive energy as triglyceride, and
the balance of lipogenesis and lipolysis is tightly regulated by
hormones, such as insulin, and the sympathetic nervous system
in response to nutritional conditions13. Adipose tissue inflam-
mation also regulates this process: macrophage-derived pro-
inflammatory cytokines can induce insulin resistance as well as
lipolysis in adipocytes. In addition, adipose tissue fibrosis might
be a novel mechanism of ectopic lipid accumulation, given that
it affects the lipid-storage capacity of adipose tissue. However,
the molecular mechanism of adipose tissue fibrosis is still
unclear.
Recently, we showed that macrophage-inducible C-type lectin
(Mincle, Clec4e or Clecsf9) is a novel regulatory factor of adi-
pose tissue fibrosis38. Mincle is a type II membrane protein in
macrophages, and functions as a pathogen sensor that
recognizes Mycobacterium tuberculosis and certain types of
fungi39–41. Recent evidence also suggests that Mincle senses cell
death to induce sterile inflammation42. In obese adipose tissue,
Mincle expression is localized to the macrophages constituting
CLS, where dead or dying adipocytes are surrounded by
macrophages. When Mincle is activated by currently unknown
endogenous ligands, which are probably released from dead or
dying adipocytes, Mincle signaling can activate fibroblast or
induce myofibroblast formation resulting in interstitial fibrosis
in adipose tissue. Indeed, obesity-induced adipose tissue fibrosis
J Diabetes Investig Vol. 9 No. 2 March 2018 257
REVIEW ARTICLE
Tanaka et al.
is attenuated in Mincle-deficient mice, which leads to less ecto-
pic lipid accumulation in the liver. For the next step, it is
important to identify the cellular origin of myofibroblasts in
obese adipose tissue. In this regard, Iwayama et al.43 reported
that activation of platelet-derived growth factor receptor-a sig-
naling perturbs differentiation of preadipocytes to induce
myofibroblast formation. As activated Mincle signaling in
macrophages markedly increases expression of platelet-derived
growth factor and transforming growth factor-b, it is interesting
to know how myofibroblast formation is regulated by Mincle
(Figures 1 and 2).
NOVEL ANIMAL MODEL OF NASH
Recently, we found that there is an adipose tissue CLS-like his-
tological structure in the liver of NASH in mice and humans17.
The ‘two-hit’ hypothesis has been proposed to explain NASH
progression from steatosis: (i) the first hit – excessive lipids
accumulation in the liver; and (ii) the second hit – additional
pathogenic stimuli, such as oxidative stress, endotoxins,
pro-inflammatory cytokines and lipotoxicity. However, the
pathogenesis of NASH is still unclear; it is partly because of the
limited availability of suitable animal models that reflect a liver
condition of human NASH44. For instance, methionine and
choline-deficient diet-fed mice develop steatosis and mild fibro-
sis, without obesity and insulin resistance. In addition, chemi-
cally-induced liver fibrosis is not accompanied by metabolic
abnormalities, such as obesity, insulin resistance and hepatic
steatosis. In this regard, our NASH model using melanocortin-
4 receptor (MC4R) deficient (MC4R-KO) mice is unique, as
MC4R-KO mice fed a high-fat diet show not only obesity,
Adipose tissue
(obesity)
M1 macrophages
Endogenous ligand
Mincle
Adipose tissue
Myofibroblasts CLS
Extracellular matrix
Figure 1 | Role of crown-like structure (CLS) in obesity-induced ‘metabolic’ tissue remodeling in adipose tissue and liver. Mincle, a novel sensor for
cell death, is exclusively expressed in the CD11c-positive macrophages constituting CLS in obese adipose tissue. When activated by currently
unknown endogenous ligands, Mincle potently induces myofibroblast formation and interstitial fibrosis. There is a similar histological structure
termed hepatic CLS in the liver during the disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH). Thus, CLS plays a
critical role in driving ‘metabolic’ tissue remodeling.
258 J Diabetes Investig Vol. 9 No. 2 March 2018
http://onlinelibrary.wiley.com/journal/jdi
insulin resistance and dyslipidemia, but also a liver condition
similar to human NASH36. They also develop multiple liver
tumors after a longer period of time. It is known that MC4R
expression is restricted to the hypothalamus and other brain
regions, and MC4R messenger ribonucleic acid is undetectable
in the liver and the adipose tissue. Based on this point of view,
it is likely that the hepatic phenotype in high-fat diet-fed
MC4R-KO mice results from loss of function of MC4R in the
brain rather than in the liver itself. Accordingly, MC4R-KO
mice would be a unique mouse model of NASH, and this
model is useful for investigating the molecular mechanism of
human NASH.
HEPATIC CLS-MEDIATED LIVER FIBROSIS IN NASH
Using our NASH model, we found hepatic CLS in the liver of
MC4R-KO mice, in which CD11c-positive macrophages sur-
round dead or dying hepatocytes with large lipid droplets17.
Hepatic CLS shares most of the histological features of adipose
tissue CLS: hepatic CLS is composed of CD11c-positive macro-
phages, and surrounded by myofibroblasts and extracellular
matrices. The number of hepatic CLS is positively correlated
with the extent of liver fibrosis17. Furthermore, hepatic CLS is a
cellular source that produces pro-inflammatory cytokines and
fibrogenic mediators. As hepatic CLS formation is observed
before the development of NASH, it is likely that hepatic CLS
is involved in the disease progression from simple steatosis to
NASH. It is noteworthy that hepatic CLS is observed in other
animal models of NASH including dietary deficiency of
methionine and choline, and long-term feeding of a high-fat
diet. Hepatic CLS is also useful to evaluate the effect of
Liver
Free fatty acids
(NASH)
Adipocytokines
Hepatic CLS
CD11c+ macrophages
Myofibroblasts
Dead cells
(adipocytes, hepatocytes)
ª 2017 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
 REVIEW ARTICLE
http://onlinelibrary.wiley.com/journal/jdi Obesity and metabolic tissue remodeling

Inflammation

Sympathetic nerve
Insulin

Lipogenesis Lipolysis
Free fatty acids

Mincle

Macrophages Ectopic lipid

Extracellular matrix accumulation
Adipose tissue

Figure 2 | Role of adipose tissue fibrosis in ectopic lipid accumulation. To store excessive energy as triglyceride is a fundamental function of
adipose tissue, which is tightly regulated by hormones, such as insulin, and the sympathetic nerve. In addition, recent evidence has suggested that
chronic inflammation is involved in this process. Particularly, interstitial fibrosis limits adipose tissue expandability, which finally leads to increased
ectopic lipid accumulation.

interventions to prevent or treat NASH. For instance, we previ-
ously reported using MC4R-KO mice that pirfenidone, a clini-
cally available antifibrotic agent for idiopathic pulmonary
fibrosis, effectively prevents the development of NASH45. Inter-
estingly, treatment with pirfenidone strongly inhibited hepatic
CLS formation and the following inflammation and fibrosis,
without affecting hepatic steatosis. These observations led us to
speculate that hepatic CLS might be a site of action of pir-
fenidone. In contrast, EPA treatment suppressed hepatic steato-
sis along with hepatic CLS formation and liver fibrosis in
MC4R-KO mice46. In addition to the prophylactic protocol,
EPA showed the effect in the therapeutic protocol, in which
EPA was administered after MC4R-KO mice developed NASH.
In this protocol, there was a marked decrease in the number of
hepatic CLS after EPA treatment. Although hepatocyte death is
considered a pathogenic feature of NASH47, it remains to be
elucidated how hepatocyte death leads to liver fibrosis. These
findings suggest that hepatic CLS drives hepatocyte death-
induced chronic inflammation and pericellular fibrosis in the
development of NASH.
CLINICAL RELEVANCE OF HEPATIC CLS IN NASH
It is important to assess the clinical implication of hepatic CLS
in human NASH. Notably, hepatic CLS was observed in liver
biopsy specimens from patients with NAFLD/NASH17. On the
basis of the NAFLD Activity Score, the number of hepatic CLS
was positively associated with the score for ballooning degener-
ation, a hallmark for hepatocyte injury. Furthermore, the num-
ber of hepatic CLS was the highest in the patients with a
NAFLD Activity Score of 5. These clinical findings are consis-
tent with our experimental data showing that hepatocyte death
triggers hepatic CLS formation, thereby inducing inflammation
and fibrosis. Interestingly, hepatic CLS was rarely observed in
patients with chronic viral hepatitis, whose serum AST and
ALT concentrations were roughly equal to those in patients
with NAFLD/NASH. Therefore, hepatic CLS would be a
NASH-specific pathological mechanism. As a future direction,
it is interesting to translate the findings based on basic research
using our NASH model into clinical practice. For instance,
secreted factors derived from hepatic CLS might be a novel bio-
marker to predict the development of NASH or reflect the dis-
ease activity of NASH. Histological examinations focusing on
hepatic CLS might also be helpful to evaluate the clinical use-
fulness of non-invasive diagnostic tools, such as ultrasound elas-
tography and magnetic resonance elastography.
CONCLUSION
For the past several decades, there has been dramatic progress
in understanding the underlying mechanism of chronic inflam-
mation in lifestyle-related diseases, such as obesity, diabetes and
NAFLD/NASH. In the present review, we discussed the recent
progress of this research field, particularly focusing on how
obesity-induced chronic inflammation leads to interstitial fibro-
sis in adipose tissue and the liver. CLS is the site of the cross-
talk between parenchymal cells and stromal cells, including
macrophages, thereby inducing persistent inflammation and
interstitial fibrosis. In other words, CLS might function to drive
‘metabolic’ tissue remodeling. Better understanding of the
molecular mechanism underlying obesity-induced chronic
inflammation would pave the way to developing a novel thera-
peutic strategy for lifestyle-related diseases, such as obesity, dia-
betes and NAFLD/NASH.
ACKNOWLEDGMENTS
This work was supported in part by Grants-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,

ª 2017 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 9 No. 2 March 2018 259
REVIEW ARTICLE
Tanaka et al.
Science and Technology of Japan (16H05171, 16KT0110,
16K08732, 17K19686 and 17H05500), and Japan Agency for
Medical Research and Development (CREST). This work was
also supported by research grants from Takeda Science Foun-
dation, Takeda Medical Research Foundation and the Joint
Usage/Research Program of Medical Research Institute, and
Tokyo Medical and Dental University.
DISCLOSURE
The authors declare no conflict of interest.
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